Cationic Steroid Microbial Compositions and Methods of Use

Abstract

The invention relates to methods for decreasing or inhibiting influenza virus infection or pathogenesis of a cell in vitro, ex vivo or in vivo, a symptom or pathology associated with influenza infection or pathogenesis in vitro, ex vivo or in vivo, or an adverse side effect of influenza infection or pathogenesis in vitro, ex vivo or in vivo. In one embodiment, a method of the invention includes treating a subject with an invention compound (e.g., cationic steroid antimicrobial or CSA).

1 . A method for providing a subject with protection against influenza virus infection or pathogenesis, comprising administering a composition comprising a sufficient amount of cationic steroid antimicrobial (CSA) to provide the subject with protection against influenza virus infection or pathogenesis.  
   
   
       2 . A method for treating a subject for influenza virus infection or pathogenesis, comprising administering a composition comprising a sufficient amount of cationic steroid antimicrobial (CSA) to treat the subject for the influenza virus infection or pathogenesis.  
   
   
       3 . A method for decreasing susceptibility of a subject to a influenza virus infection or pathogenesis, comprising administering a composition comprising a sufficient amount of cationic steroid antimicrobial (CSA) to decrease susceptibility of the subject to influenza virus infection or pathogenesis.  
   
   
       4 . The method of any of  claims 1  to  3 , wherein the CSA is administered prior to, concurrently with, or following infection of the subject with or exposure of the subject to influenza virus.  
   
   
       5 . The method of any of  claims 1  to  3 , wherein the CSA is administered prior to, concurrently with, or following development of a symptom of influenza virus infection.  
   
   
       6 . The method of any of  claims 1  to  3 , wherein the influenza virus comprises a pathogenic influenza A, B or C virus.  
   
   
       7 . The method of any of  claims 1  to  3 , wherein the influenza virus is selected from A/PR/34, A/HK/8/68, A/H1/68, H1N1, H2N2, H3N2, H5N1, H9N2, H2N1, H4N6, H6N2, H7N2, H7N3, H4N8, H5N2, H2N3, H11N9, H3N8, H1N2, H11N2, H11N9, H7N7, H2N3, H6N1, H13N6, H 7 N1, H11N1, H7N2 and H5N3.  
   
   
       8 . The method of any of  claims 1  to  3 , wherein the CSA is selected from CSA-7, CSA-8, CSA-10, CSA-1, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 .  
   
   
       9 . The method of any of  claims 1  to  3 , wherein the CSA does not have a charged group at position C24.  
   
   
       10 . The method of any of  claims 1  to  3 , wherein the CSA has a hydrophobic moiety at position C24.  
   
   
       11 . The method of  claim 10 , wherein the hydrophobic moiety at position C24 comprises a lipid.  
   
   
       12 . The method of any of  claims 1  to  3 , wherein the CSA has a charged group at position C7.  
   
   
       13 . The method of any of  claims 1  to  3 , wherein the CSA comprises a multimer.  
   
   
       14 . The method of any of  claims 1  to  3 , wherein the CSA multimer comprises a dimer, trimer, or tetramer.  
   
   
       15 . The method of any of  claims 1  to  3 , wherein the CSA has a shorter tether length between the steroid scaffold and the amine groups at positions C3, C7 and C12, relative to the tether length of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 or CSA-59, as set forth in  FIG. 10 .  
   
   
       16 . The method of any of  claims 1  to  3 , wherein the CSA comprises a pharmaceutically acceptable carrier or excipient.  
   
   
       17 . The method of any of  claims 1  to  3 , wherein the CSA comprises a sterile formulation.  
   
   
       18 . The method of any of  claims 1  to  17 , wherein the subject is provided with partial or complete protection against an influenza virus infection or pathogenesis, or a symptom of an influenza virus infection or pathogenesis.  
   
   
       19 . The method of any of  claims 1  to  17 , wherein the method reduces, decreases, inhibits, ameliorates or prevents onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis in a subject.  
   
   
       20 . The method of  claim 19 , wherein the symptom is selected from: chills, fever, cough, sore throat, nasal congestion, sinus congestion, nasal infection, sinus infection, body ache, head ache, fatigue, pneumonia, bronchitis, ear infection, ear ache and death.  
   
   
       21 . The method of any of  claims 1  to  17 , wherein the method hastens recovery from an influenza virus infection.  
   
   
       22 . The method of any of  claims 1  to  17 , wherein the method reduces or decreases influenza virus titer, replication proliferation or a viral protein, or inhibits or prevents increases in influenza virus titer, replication, proliferation or a viral protein.  
   
   
       23 . The method of any of  claims 1  to  17 , wherein the method reduces or decreases susceptibility of the subject to influenza virus infection or one or more symptoms associated with influenza virus infection or pathogenesis.  
   
   
       24 . The method of any of  claims 1  to  17 , wherein the subject has not been infected with or exposed to influenza virus.  
   
   
       25 . The method of any of  claims 1  to  17 , wherein the subject has been infected with or exposed to influenza virus.  
   
   
       26 . The method of any of  claims 1  to  17 , wherein the subject is a candidate for or has been vaccinated with a live or attenuated influenza virus.  
   
   
       27 . The method of any of  claims 1  to  17 , wherein the subject is immunocompromised.  
   
   
       28 . The method of any of  claims 1  to  17 , wherein the subject has been exposed to or diagnosed as HIV+.  
   
   
       29 . The method of any of  claims 1  to  17 , wherein the subject is a candidate for or has received an immunosuppressant treatment.  
   
   
       30 . The method of any of  claims 1  to  17 , wherein the subject is a candidate for or has received a tissue or organ transplant.  
   
   
       31 . The method of any of  claims 1  to  17 , wherein the subject is a newborn, infant, toddler or child.  
   
   
       32 . The method of any of  claims 1  to  17 , wherein the subject is 50 years or older.  
   
   
       33 . The method of any of  claims 1  to  17 , further comprising administering to the subject an additional CSA or influenza virus treatment.  
   
   
       34 . The method of  claim 33 , wherein the additional treatment comprises a neuraminidase inhibitor.  
   
   
       35 . The method of  claim 33 , wherein the additional treatment comprises amantadine, Oseltamivir (Tamiflu), Zanamivir, or rimantadine.  
   
   
       36 . The method of  claim 33 , wherein the additional treatment comprises an antibody that binds to an influenza virus protein.  
   
   
       37 . The method of  claim 36 , wherein the antibody is human, humanized or chimeric.  
   
   
       38 . The method of  claim 36 , wherein the antibody is monoclonal or polyclonal.  
   
   
       39 . A method for decreasing or inhibiting influenza virus infection of a cell in vitro or in vivo, comprising administering a composition comprising a sufficient amount of cationic steroid antimicrobial (CSA) to inhibit influenza virus infection of the cell.  
   
   
       40 . The method of  claim 39 , wherein the cell is mammalian.  
   
   
       41 . The method of  claim 39 , wherein the cell is human.  
   
   
       42 . A method for providing a subject with protection against an influenza virus infection or pathogenesis, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to provide the subject with protection against the influenza virus infection or pathogenesis.  
   
   
       43 . A method for treating a subject for an influenza virus infection or pathogenesis, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to treat the subject for the influenza virus infection or pathogenesis.  
   
   
       44 . A method for decreasing susceptibility of a subject to an influenza virus infection or pathogenesis, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to decrease susceptibility of the subject to an influenza virus infection or pathogenesis.  
   
   
       45 . A method for reducing, decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis in a subject, comprising administering a sufficient amount of CSA-7, CSA-8, CSA-10, CSA-11, CSA-13, CSA-15, CSA-17, CSA-21, CSA-25, CSA-26, CSA-31, CSA-46, CSA-54 and CSA-59, as set forth in  FIG. 10 , to decrease, inhibit, ameliorate or prevent onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis in the subject.  
   
   
       46 . A kit, said kit comprising packaging material, a cationic steroid antimicrobial (CSA) and instructions, said instructions comprising administering said CSA to: 
 a) provide a subject with protection against an influenza virus infection or pathogenesis;    b) treat a subject for influenza virus infection or pathogenesis;    c) decrease susceptibility of a subject to an influenza virus infection or pathogenesis; or    d) decrease, inhibit, ameliorate or prevent onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis.    
   
   
       47 . A method for identifying a candidate agent for treating a subject for an influenza virus infection or pathogenesis, comprising: 
 a) providing a test agent, said test agent comprising a cationic steroid antimicrobial (CSA);    b) contacting said test agent with influenza virus and ascertaining whether the test agent inhibits influenza virus infection or pathogenesis, wherein a test agent identified as inhibiting influenza virus infection or pathogenesis is a candidate agent for treating a subject for influenza virus infection or pathogenesis.    
   
   
       48 . A method for identifying a candidate agent for decreasing susceptibility of a subject to an influenza virus infection or pathogenesis, comprising: 
 a) providing a test agent, said test agent comprising a cationic steroid antimicrobial (CSA);    b) contacting said test agent with influenza virus and ascertaining whether the test agent inhibits influenza virus infection or pathogenesis, wherein a test agent identified as inhibiting influenza virus infection or pathogenesis is a candidate agent for decreasing susceptibility of a subject to an influenza virus infection or pathogenesis.    
   
   
       49 . A method for identifying a candidate agent for decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis, comprising: 
 a) providing a test agent, said test agent comprising a cationic steroid antimicrobial (CSA);    b) administering said test agent to a subject infected with or exposed to influenza virus and ascertaining whether the test agent decreases, inhibits, ameliorates or prevents onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis, wherein a test agent identified is a candidate agent for decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of one or more symptoms associated with influenza virus infection or pathogenesis.    
   
   
       50 . The method of  claim 49 , wherein the subject comprises a mammal.  
   
   
       51 . The method of  claim 50 , wherein the mammal comprises an animal model for influenza virus infection or pathogenesis.